title: Cellular antioxidant adaptive survival response to 6-hydroxydopamine-induced nitrosative cell death in C6 glioma cells.
abstract: Parkinson's disease (PD) is a progressive neurodegenerative movement disorder characterized by selective loss of dopaminergic neurons in the substantia nigra. 6-Hydroxydopamine (6-OHDA) is a catecholaminergic neurotoxin widely used to produce experimental models of PD and has been reported to cause oxidative and/or nitrosative stress. In this study, we have investigated 6-OHDA-induced nitrosative cell death and its self-defense mechanism in C6 glioma cells. Treatment of C6 cells with 6-OHDA increased expression of inducible nitric oxide synthase (iNOS) and subsequent production of nitric oxide (NO). Furthermore 6-OHDA treatment led to peroxynitrite generation and nitrotyrosine formation. 6-OHDA-induced nitrosative stress ultimately caused apoptotic cell death as determined by decreased Bcl-2/Bax ratio, activation of c-Jun N-terminal kinase (JNK), and cleavage of caspase-3 and poly(ADP-ribose)polymerase (PARP), which were attenuated by peroxynitrite decomposition catalyst, 5,10,15,20-tetrakis(4-sulfonatophenyl)prophyrinato iron(III) (FeTPPS). In another experiment, exposure of C6 glioma cells to 6-OHDA resulted in an increased expression of heme oxygenase-1 (HO-1) and 6-OHDA-induced cytotoxicity was effectively suppressed by the HO-1 inducer SnCl(2) and aggravated by HO-1 inhibitor zinc protoporphyrin (ZnPP), supporting the cytoprotective role of HO-1. To elucidate the molecular mechanism underlying 6-OHDA-mediated HO-1 induction, we have examined the possible involvement of NF-E2-related factor 2 (Nrf2), which plays an important role in the transcriptional regulation of phase II detoxifying and antioxidant enzymes. 6-OHDA treatment increased nuclear translocation and transcriptional activity of Nrf2, which seemed to be partly mediated by activation of upstream kinases such as Akt/protein kinase B (PKB). Taken together these findings suggest that HO-1 up-regulation via Nrf2 activation may mediate the cellular adaptive survival response to 6-OHDA-induced nitrosative cell death in C6 glioma cells.
authors.affiliation: College of Oriental Medicine, Daegu Haany University, Daegu 706-828, South Korea.
authors.forename: Chan
authors.initials: C
authors.lastname: Lee
authors.forename: Gyu Hwan
authors.initials: GH
authors.lastname: Park
authors.forename: Jung-Hee
authors.initials: JH
authors.lastname: Jang
mesh_terms: D000975:Antioxidants / Q000378:metabolism*; D015153:Blotting, Western; D002470:Cell Survival / Q000187:drug effects*; D004396:Coloring Agents; D005910:Glioma / Q000473:pathology; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006801:Humans; D006892:Hydroxydopamines / Q000494:pharmacology; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008156:Luciferases / Q000096:biosynthesis / Q000235:genetics; D051267:NF-E2-Related Factor 2 / Q000096:biosynthesis / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D011166:Porphyrins / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000235:genetics; D026361:Reactive Nitrogen Species / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation
chemical_list: D000975:Antioxidants; D004396:Coloring Agents; D006892:Hydroxydopamines; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D009419:Nerve Tissue Proteins; D011166:Porphyrins; D026361:Reactive Nitrogen Species; D009569:Nitric Oxide; C016136:tetraphenylporphine sulfonate; D008156:Luciferases; D051547:Heme Oxygenase-1